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PMID:20553714

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Citation

Sahenk, Z, Galloway, G, Edwards, C, Malik, V, Kaspar, BK, Eagle, A, Yetter, B, Forgie, A, Tsao, D and Lin, JC (2010) TrkB and TrkC agonist antibodies improve function, electrophysiologic and pathologic features in Trembler J mice. Exp. Neurol. 224:495-506

Abstract

Neurotrophic factors have been considered as potential therapeutics for peripheral neuropathies. Previously, we showed that neurotrophin-3 (NT-3) promotes nerve regeneration in Trembler(J) (Tr(J)) mice and in sural nerves from patients with Charcot-Marie-Tooth 1A (CMT1A). The relatively short plasma half-life of NT-3 and other neurotrophins, however, pose a practical difficulty in their clinical application. Therapeutic agonist antibodies (AAb) targeting the neurotrophic receptors may circumvent this obstacle due to their high specificity and long half-life. Using morphological, electrophysiological studies and functional motor testing, we assessed the efficacy of monoclonal TrkC AAb and TrkB AAb in the Tr(J) mice. Treatments of these AAbs individually or in combination over 20 weeks increased compound muscle action potential (CMAP) amplitude, which correlated with improved grip strength, as compared to the PBS control group. Improvements in CMAP amplitude were most prominent with TrkC AAb treatment. In all treatment groups, distal to the crush site of the sciatic nerves exhibited a significantly greater number of myelinated fibers (MFs) indicating improved regenerative response to injury. In the contralateral intact sciatic nerves, the number of MFs as well as the myelin thickness was also increased significantly by the AAb treatments, suggesting that the hypomyelination/amyelination state of the peripheral nerves in Tr(J) improved. Therapeutic response to AAb combination was often, albeit not always, the most prominent, indicating a non-redundant effect of TrkB and TrkC AAbs. An early functional recovery and the correlative morphological changes of enhanced regeneration were seen with TrkC AAb treatment. These results provide evidence for potential therapeutic use of monoclonal agonist antibodies for neurotrophin receptors in CMT1A and other neuropathies.

Links

PubMed Online version:10.1016/j.expneurol.2010.05.013

Keywords

Animals; Antibodies, Monoclonal/pharmacokinetics; Antibodies, Monoclonal/pharmacology; CHO Cells; Charcot-Marie-Tooth Disease/genetics; Charcot-Marie-Tooth Disease/pathology; Charcot-Marie-Tooth Disease/physiopathology; Cricetinae; Cricetulus; Disease Models, Animal; Hand Strength; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Motor Skills; Muscle Fibers, Skeletal/drug effects; Muscle Fibers, Skeletal/pathology; Mutation, Missense; Myelin Proteins/genetics; Myelin Sheath/metabolism; Nerve Crush; Nerve Regeneration; Neural Conduction; Rats; Receptor, trkB/agonists; Receptor, trkB/immunology; Receptor, trkC/agonists; Receptor, trkC/immunology; Schwann Cells/metabolism; Schwann Cells/pathology; Sciatic Nerve/metabolism; Sciatic Nerve/pathology; Sciatic Nerve/physiopathology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NTRK2

acts_upstream_of_or_within

GO:0022011: myelination in peripheral nervous system

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97385
MGI:MGI:97631

P

Seeded From UniProt

complete

MOUSE:NTRK2

acts_upstream_of_or_within

GO:0019227: neuronal action potential propagation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97385
MGI:MGI:97631

P

Seeded From UniProt

complete

MOUSE:NTRK3

acts_upstream_of_or_within

GO:0022011: myelination in peripheral nervous system

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97384
MGI:MGI:97631

P

Seeded From UniProt

complete

MOUSE:NTRK3

acts_upstream_of_or_within

GO:0019227: neuronal action potential propagation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97384
MGI:MGI:97631

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0019226: transmission of nerve impulse

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97384
MGI:MGI:97385

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0022011: myelination in peripheral nervous system

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856217

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0022011: myelination in peripheral nervous system

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97384
MGI:MGI:97385

P

Seeded From UniProt

complete

Notes

See also

References

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